Summary
Background
Risk stratification in asymptomatic patients with severe aortic stenosis (AS) is based on exercise test results. However, differentiating between pathological and physiological breathlessness during exercise is sometimes challenging. Cardiopulmonary exercise testing (CPET) may improve quantification of cardiopulmonary exercise capacity in patients with valve diseases.
Aims
To assess the ability of CPET to detect abnormal responses to exercise and a clinical endpoint (occurrence of European Society of Cardiology guidelines surgical class I triggers).
Methods
Forty-three consecutive patients (mean age 69 ± 13 years; 31 men) with no reported symptoms and severe AS (aortic valve surface area < 1 cm 2 or indexed aortic valve surface area ≤ 0.6 cm 2 /m 2 ) prospectively underwent symptom-limited CPET.
Results
Twelve (28%) patients had an abnormal exercise test (AET) with symptoms (abnormal dyspnoea n = 11; angina n = 1). Both VE/VCO 2 slope > 34 (hazard ratio [HR] = 5.76, 95% confidence interval [CI] 1.086–30.587; P = 0.04) and peak VO 2 ≤ 14 mL/kg/min (HR 6.01, 95% CI 1.153–31.275; P = 0.03) were independently associated with an AET. Furthermore, VE/VCO 2 slope > 34 (HR 3.681, 95% CI 1.318–10.286; P = 0.013) and peak VO 2 ≤ 14 mL/kg/min (HR 3.058, 95% CI 1.074–8.713; P = 0.036) were independent predictors of reaching the clinical endpoint.
Conclusions
Cardiopulmonary exercise testing is a useful tool for characterizing breathlessness during an exercise test in apparently asymptomatic patients with AS. Peak VO 2 ≤ 14 mL/kg/min and VE/VCO 2 slope > 34 were associated with an AET and the occurrence of European Society of Cardiology guideline surgical class I triggers.
Résumé
Contexte
L’épreuve d’effort en cas de sténose aortique serrée asymptomatique d’après l’interrogatoire vise à démasquer la survenue de symptômes. Néanmoins, il est parfois difficile de différentier un essoufflement à l’effort pathologique d’un essoufflement physiologique.
Objectifs
Évaluer la capacité de l’épreuve d’effort cardiorespiratoire chez les patients atteints d’une sténose aortique serrée asymptomatique d’après l’interrogatoire à (i) détecter une réponse anormale à l’effort, (ii) à prédire un objectif clinique (la survenue d’une indication opératoire de classe I selon la Société européenne de cardiologie).
Méthodes
Une épreuve d’effort cardiorespiratoire a été réalisée prospectivement chez quarante-trois patients consécutifs (d’âge moyen 69 ± 13 ans ; 32 hommes) porteurs d’une sténose aortique serrée (surface aortique < 1 cm 2 ou surface aortique indexée ≤ 0,6 cm 2 /m 2 ) sans symptôme rapporté à l’interrogatoire.
Résultats
Douze patients (28 %) ont présenté des symptômes lors du test d’effort (dyspnée anormale n = 11 ; angor n = 1). Une pente VE/VCO 2 > 34 (hazard ratio [HR] 5,76, 95 % intervalle de confiance [IC] 1,086–30,587 ; p = 0,04) et un pic de VO 2 ≤ 14 mL/kg/min (HR 6,01, 95 % IC 1,153–31,275 ; p = 0,03) étaient indépendamment associés avec la survenue de symptômes lors de l’épreuve d’effort. De plus, une pente VE/VCO 2 > 34 (HR 3,681, 95 % IC 1,318–10,286 ; p = 0,013) et un pic de VO 2 ≤ 14 mL/kg/min (HR 3,058, 95 % IC 1,074–8,713 ; p = 0,036) étaient associés à une indication chirurgicale de classe I.
Conclusions
L’épreuve d’effort cardiorespiratoire peut s’avérer utile pour définir le caractère pathologique d’une dyspnée lors d’un test d’effort dans le cadre d’une sténose aortique serrée censée être asymptomatique selon l’interrogatoire. Un pic de VO 2 ≤ 14 mL/kg/min et une pente VE/VCO 2 > 34 sont associés à la survenue de symptôme lors du test d’effort et à une indication chirurgicale de classe I de l’ESC.
Background
The indication for aortic valve replacement (AVR) in asymptomatic patients with aortic stenosis (AS) is subject to debate. ‘Watchful waiting’ may expose the patient to the risk of sudden cardiac death, whereas early AVR is associated with significant per- and postoperative morbimortality and potential prosthetic valve complications. Along with the rare case of severe AS associated with the left ventricular ejection fraction < 50%, the recent European Society of Cardiology and American College of Cardiology/American Heart Association guidelines suggest the use of risk stratification based on the prediction of rapid worsening of the AS and exercise test results. However, non-specific dyspnoea is frequently observed during exercise testing, and differentiating between pathological and physiological breathlessness is sometimes challenging. Indeed, aging, a sedentary lifestyle, obesity and/or lung disease complicate the interpretation of exercise symptoms.
Cardiopulmonary exercise testing (CPET) has proven diagnostic and prognostic value in heart failure and reportedly improves the quantification of exercise cardiopulmonary capacity in valve diseases . Indeed, CPET enables the exhaustive, reproducible and objective quantification of exercise capacity in healthy patients. Several cardiopulmonary variables can be monitored as a guide to ventilatory and cardiac efficiencies. Peak oxygen uptake (peak VO 2 ) was first described as a strong predictor of outcome in systolic heart failure . More recently, other ventilatory expired gas variables obtained during CPET (such as ventilation [VE]/carbon dioxide output [VCO 2 ] slope) have been suggested as severity markers in heart failure . It was recently reported that symptom-limited exercise testing and CPET were safe in asymptomatic AS, and that the ejection fraction was not affected . However, there are no published data on the value of CPET for detecting abnormal responses to exercise or the development of symptoms during follow-up in patients with apparently asymptomatic AS.
Methods
Study population
Forty-three consecutive patients with no reported cardiological symptoms, an ejection fraction > 50% and severe AS (aortic valve surface area < 1 cm 2 or indexed aortic valve surface area ≤ 0.6 cm 2 /m 2 ) prospectively underwent symptom-limited CPET. Patients unable to perform adequate physical exercise and those with significant aortic regurgitation, severe mitral regurgitation or stenosis were excluded from the study. The physician in charge of the patient was aware of the results of the exercise testing but was blinded to the CPET results. Coronary angiography had been performed in 57% of the patients. Severe coronary artery stenosis was defined as a reduction of ≥ 50% in the normal diameter of the left main coronary artery and a reduction of ≥ 70% in the right coronary, left anterior descending and circumflex arteries. Multivessel coronary artery disease was defined as significant stenosis in two or more vessels. The study was approved by the local independent ethics committee. All patients gave their written informed consent prior to participation in any study procedures.
Echocardiography
Commercially available ultrasound machines were used to perform comprehensive echocardiography (including measurement of the aortic valve surface area) in all patients . Left ventricular ejection fraction was estimated with Simpson’s rule . Left ventricle and left atrium dimensions were measured according to the American Society of Echocardiography/European Association of Echocardiography guidelines . Valvuloarterial impedance was calculated as Zva = (SAP + MPG)/SVI, where SAP is the systolic arterial pressure, MPG is the mean transaortic pressure gradient and SVI is the stroke volume index . Left ventricular mass was calculated according to the American Society of Echocardiography formula and normalized against body surface area. Resting left ventricular diastolic function was assessed from the mitral inflow (E- and A-wave velocities, the deceleration time of the E-wave and the E/A ratio). Early diastolic pulsed-wave tissue Doppler annular velocity (e’) at rest was also measured at the septal and lateral side of the annulus, and was averaged to calculate the E/e’ ratio. Tricuspid valve regurgitation velocity was measured. Pulmonary artery systolic pressure was estimated at rest, using the simplified Bernoulli equation and adding an estimated right atrial pressure.
Cardiopulmonary exercise testing
Symptom-limited CPET was performed on an upright cycle ergometer in all cases. The workload protocol was chosen so that maximal effort was achieved within 8–12 minutes. Exercise workload was increased by a ramp protocol (20 W/min or 10 W/min) after a 1-minute warm-up at 20 W. Patients were encouraged to exercise to exhaustion. A 12-lead electrocardiogram (Cardiac Assessment System for Exercise Testing; GE Healthcare, Waukesha, WI, USA) was continuously monitored during exercise and for at least 5 minutes during the post-test recovery phase. Blood pressure was measured at rest and every 2 minutes during exercise. Patients were allowed to take their usual medication on the day of the CPET. Ventilatory expired gas was analysed with a Masterscreen CPX system (Viasys Healthcare, Jaeger, Germany), calibrated with reference gases before each test. Breath-by-breath gas exchange data were recorded and then averaged over 30-second time periods. Peak VO 2 was defined as the highest consecutive 30-second averaged value obtained during exercise; it was normalized and expressed as a percentage of age-, sex- and body weight-predicted values. The VE/VCO 2 slope was calculated by linear regression. The respiratory exchange ratio (RER) was defined as VCO 2 /VO 2 . An abnormal exercise test (AET) was defined as a test with: the occurrence of symptoms, such as limiting breathlessness or fatigue at low workload, angina, dizziness or syncope; an abnormal blood pressure response (defined as a peak systolic blood pressure at or below the baseline level); or complex ventricular arrhythmia. The maximum workload was recorded and the percentage of maximum age- and sex-predicted workload was calculated . Each patient was carefully questioned and observed during the recovery phase, in order to differentiate between abnormal and normal breathlessness. Abnormal breathlessness appeared early (i.e. at a low level of exercise relative to predicted performance) and prevented the patient from speaking for several minutes. Normal breathlessness appeared at an expected time point during CPET and disappeared quickly during the post-exercise recovery phase.
Clinical follow-up
Patients were followed up every 6 months by their cardiologist (mean duration of follow-up 28 ± 31 months). The clinical endpoint was defined as the occurrence of 2007 European Society of Cardiology guidelines surgical class I triggers (i.e. an AET with symptoms [class IC] or the development of cardiac symptoms related to AS [dyspnoea, syncope or angina] during follow-up [class IB]). All patients reaching the clinical endpoint were referred for AVR, in accordance with the European Society of Cardiology guidelines .
Statistical analysis
Continuous variables are expressed as mean ± standard deviation and categorical variables as count (percentage). Intergroup comparisons of categorical variables were performed with a chi 2 test or Fisher’s exact test (when required). Student’s t test or Wilcoxon’s rank-sum test were used as appropriate for continuous variables. Receiver operating characteristic (ROC) curve analysis was used to identify the best cut-off values of peak VO 2 and VE/VCO 2 slope for predicting AET. In multivariable analyses, a Cox proportional hazards model was used to study the occurrence of clinical endpoint within 24 months of CPET and logistic regression was used to analyse CPET predictors of AET with symptoms. In univariate analysis, the threshold for selecting variables for a multivariable analysis was set at P < 0.10. Survival curves were plotted according to the Kaplan–Meier method and differences were tested with the log-rank test. The threshold for statistical significance was set at P < 0.05.
Results
Clinical characteristics of the study population and exercise test results
The population comprised of 43 consecutive patients (mean age 69 ± 13 years), 31 of whom were men. Clinical, echocardiographic and angiographic data are presented in Table 1 . The mean aortic valve surface area, mean transvalvular gradient and ejection fraction were 0.86 ± 0.20 cm 2 , 46 ± 15 mmHg and 62 ± 7%, respectively. Associated chronic obstructive pulmonary disease and peripheral artery disease were present in 8/44 (18%) patients and 1/44 (2%) patients, respectively. B-type natriuretic peptide and serum creatinine were available in 25/44 (57%) patients and 36/44 (82%) patients, with mean values of 336 ± 47 pg/mL and 96 ± 41 μmol/L, respectively. The mean maximal exercise capacity was 98 ± 38 W (range 44–196 W). Thirteen (30%) patients had exercised-induced ST depression in one or more leads during exercise. Six patients had an ST depression of ≤ 1 mm and seven patients had an ST depression of > 1 mm. In two cases, electrocardiographic changes were not interpretable because of resting left bundle branch block. During exercise, none of the patients displayed syncope or a fall in blood pressure below the baseline. There were no major cardiovascular events during or after the test.
| Total population | Abnormal exercise test | P | ||
|---|---|---|---|---|
| Variable | Yes | No | ||
| ( n = 43) | ( n = 12) | ( n = 31) | ||
| Age (years) | 69 ± 13 | 74 ± 9 | 67 ± 14 | 0.10 |
| Men | 31 (72) | 9 (75) | 22 (71) | 0.79 |
| Body surface area (kg/m 2 ) | 1.91 ± 0.19 | 1.88 ± 0.12 | 1.92 ± 0,21 | 0.53 |
| Hypertension | 32 (74) | 10 (83) | 22 (71) | 0.7 |
| Diabetes mellitus | 10 (23) | 2 (17) | 8 (26) | 0.7 |
| Dyslipidaemia | 19 (44) | 7 (58) | 12 (39) | 0.24 |
| Beta-blocker treatment | 18 (42) | 6 (50) | 12 (39) | 0.5 |
| Statin treatment | 20 (47) | 5 (42) | 15 (48) | 0.69 |
| ACE inhibitor treatment | 26 (61) | 7 (58) | 19 (62) | 0.86 |
| Coronary angiography | 24 (56) | 12 (100) | 12 (39) | 0.0001 |
Ventilatory response in patients with abnormal exercise test
Twelve (28%) patients stopped the test because of the occurrence of symptoms (abnormal dyspnoea n = 11; angina n = 1); indication for AVR was established in these 12 cases. The remaining 31 patients stopped for fatigue or achievement of maximal heart rate. The effort was generally maximal, as 32/43 (74%) patients achieved an RER > 1.15 (mean RER 1.17 ± 0.11). The AETs were associated with a significantly lower percentage of age-predicted maximal heart rate and exercise maximum workload ( Table 1 ). Mean peak VO 2 was 16.7 ± 5.0 mL/kg/min (range 11–31 mL/kg/min). Cardiopulmonary exercise testing showed an objectively reduced exercise capacity (peak VO 2 < 80% of predicted value) in 28/43 (65%) patients. A peak VO 2 ≤ 14 mL/kg/min was found in 18/43 (42%) patients. ROC curve analysis identified values for peak VO 2 and VE/VCO 2 slope of 14 mL/kg/min and 34, respectively, as the best cut-offs for the prediction of AET (72% and 58% sensitivity, 75% and 78% specificity, area under the curve 0.76 and 0.77, respectively) ( Figs. 1 and 2 ). In univariate analysis ( Tables 1 and 2 ), the four CPET variables significantly associated with an AET were peak VO 2 , peak VO 2 ≤ 14 mL/kg/min, percentage of peak VO 2 predicted and VE/VCO 2 slope. There was a weak correlation between peak VO 2 and the VE/VCO – slope (r–0.28; P = 0.07) ( Fig. 3 ). Among the 24 patients who had coronary angiography, multivessel coronary disease was not associated with an AET. In multivariable analysis, VE/VCO 2 slope > 34 (hazard ratio [HR] 5.76, 95% confidence interval [CI] 1.086–30.587; P = 0.04) and peak VO 2 ≤ 14 mL/kg/min (HR 6.01, 95% CI 1.153–31.275; P = 0.03) were independently associated with an AET.
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